NM_000481.4(AMT):c.280C>T (p.Arg94Trp) AND Non-ketotic hyperglycinemia

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000674000.10

Allele description [Variation Report for NM_000481.4(AMT):c.280C>T (p.Arg94Trp)]

NM_000481.4(AMT):c.280C>T (p.Arg94Trp)

Gene:

AMT:aminomethyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_000481.4(AMT):c.280C>T (p.Arg94Trp)

HGVS:

NC_000003.12:g.49421551G>A
NG_015986.1:g.6128C>T
NG_033046.1:g.12774C>T
NM_000481.4:c.280C>TMANE SELECT
NM_001164710.2:c.280C>T
NM_001164711.2:c.112C>T
NM_001164712.2:c.280C>T
NP_000472.2:p.Arg94Trp
NP_000472.2:p.Arg94Trp
NP_001158182.1:p.Arg94Trp
NP_001158183.1:p.Arg38Trp
NP_001158184.1:p.Arg94Trp
LRG_537t1:c.280C>T
LRG_537:g.6128C>T
LRG_537p1:p.Arg94Trp
NC_000003.11:g.49458984G>A
NM_000481.3:c.280C>T
NM_000481.4:c.280C>T
NR_028435.2:n.289C>T

Protein change:

R38W

Links:

dbSNP: rs1126422

NCBI 1000 Genomes Browser:

rs1126422

Molecular consequence:

NM_000481.4:c.280C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164710.2:c.280C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164711.2:c.112C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164712.2:c.280C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_028435.2:n.289C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Non-ketotic hyperglycinemia
Synonyms:: Glycine encephalopathy; Nonketotic hyperglycinemia
Identifiers:: MONDO: MONDO:0011612; MedGen: C0751748; Orphanet: 407; OMIM: PS605899; Human Phenotype Ontology: HP:0008288

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000799268	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Apr 7, 2018)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28244183, 26179960, 27362913, 15272469 Citation Link,
SCV001520700	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 15, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001586710	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26179960, 27362913, 28244183, 28492532
SCV001810263	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002081721	Natera, Inc.	no assertion criteria provided	Pathogenic (Jun 24, 2021)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Glycine encephalopathy (nonketotic hyperglycinaemia) : review and update.

Applegarth DA, Toone JR.

J Inherit Metab Dis. 2004;27(3):417-22. Review.

PubMed [citation]

PMID:: 15272469

Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia.

Swanson MA, Coughlin CR Jr, Scharer GH, Szerlong HJ, Bjoraker KJ, Spector EB, Creadon-Swindell G, Mahieu V, Matthijs G, Hennermann JB, Applegarth DA, Toone JR, Tong S, Williams K, Van Hove JL.

Ann Neurol. 2015 Oct;78(4):606-18. doi: 10.1002/ana.24485. Epub 2015 Aug 10. Erratum in: Ann Neurol. 2016 Mar;79(3):505. doi: 10.1002/ana.24600.

PubMed [citation]

PMID:: 26179960
PMCID:: PMC4767401

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000799268.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001520700.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001586710.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 94 of the AMT protein (p.Arg94Trp). This variant is present in population databases (rs1126422, gnomAD 0.009%). This missense change has been observed in individual(s) with non-ketotic hyperglycinemia (PMID: 26179960, 27362913, 28244183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 557814). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AMT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001810263.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002081721.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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